Progression from Acute to Chronic Disease in a Murine Parent-into-F1 Model of Graft-Versus-Host Disease

Abstract

The parent-into-immunocompetent-F1 model of graft-vs-host disease (GVHD) induces immune dysregulation, resulting in acute or chronic GVHD. The disease outcome is thought to be determined by the number of parental anti-F1 CTL precursor cells present in the inoculum. Injection of C57BL/6 (B6) splenocytes into (B6 × DBA/2)F1 (B6D2F1) mice (acute model) leads to extensive parental cell engraftment and early death, whereas injection of DBA/2 cells (chronic model) results in little parental cell engraftment and a lupus-like disease. This study demonstrated that injection of BALB/c splenocytes into (BALB/c × B6)F1 (CB6F1) mice resulted in little engraftment of parental lymphocytes and the development of lupus as expected. Injection of B6 splenocytes into CB6F1 initiated an initial burst of parental cell engraftment similar to that of B6 into B6D2F1. However, the acute disease resolved, and the CB6F1 mice went on to develop chronic GVHD with detectable Abs to ssDNA, dsDNA, and extractable nuclear Ags. Limiting dilution CTL assays determined that B6 splenocytes have CTL precursor frequencies of 1/1000 against both CB6F1 and B6D2F1, whereas DBA/2 and BALB/c splenocytes have a CTL precursor frequency of 1/20,000 for their respective F1s. The Th cell precursor frequency for B6 anti-DBA/2 was 3-fold higher than that for B6 anti-BALB/c determined by limiting dilution proliferation assays. These results indicate the importance of adequate allospecific helper as well as effector T cells for the induction and maintenance of acute GVHD in this model, and presents an unexpected model in which initial acute GVHD is replaced by the chronic form of disease.

Unexpected Role of B and T Lymphocyte Attenuator in Sustaining Cell Survival during Chronic Allostimulation

“…Although GVHD induced in CB6F 1 mice is generally similar to that in B6D2F 1 , as described above, strain-dependent differences have been identified. BALB/c-into-CB6F 1 resulted in chronic GVHD that was comparable to that of DBA/2-into-B6D2F 1 (26). The aGVHD resulting from C57BL/6-into-CB6F 1 , characterized by donor cell expansion and antihost CTL activity, was similar to that in C57BL/6-into-B6D2F 1 during the first 3 wk following transfer (26).…”

“…In this model, transfer of C57BL/6 donor cells into C57BL/6 ϫ BALB/c F 1 (CB6F 1 ; H-2 b/d ) yields aGVHD, whereas BALB/c donor cells produce chronic GVHD (26). Although GVHD induced in CB6F 1 mice is generally similar to that in B6D2F 1 , as described above, strain-dependent differences have been identified.…”

Alloreactive CD4 T lymphocytes responsible for acute and chronic graft‐versus‐host disease are contained within the CD45RChigh but not the CD45RClow subset

“…High frequency of alloreactive lymphocytes, the engraftment of parental anti-F1 CTL and the production of type-1 cytokines favor the development of acute GvHD, while chronic GvHD is characterized by a low frequency of alloreactive lymphocytes, the absence of host CD8 engraftment and the production of type-2 cytokines [26][27][28][29][30]. In response to allogeneic stimulation in vitro, LEW and BN alloreactive CD45RC high CD4 T cells exhibited different profiles of cytokine production and proliferation.…”

Subclinical GvHD in non-irradiated F1 hybrids: severe lymphoid-tissue GvHD causing prolonged immune dysfunction

“…Reportedly, highdose C57BL/6 splenocytes induce acute epithelial GvHD that is lethal over several months. 14 In contrast, high-dose C57BL/6 LN cells induces a BMGvHD, which is rapidly lethal; [15][16][17] BMGvHD is also seen if recipients are irradiated, in which case lower quantities of C57BL/6 T cells are required. Here, we found that challenge of B6DBA2F1 with C57BL/6 splenocytes gave rise to two distinct outcome patterns.…”

“…12,13 Earlier studies in the C57BL/6-B6DBA2F1 model showed that high-dose C57BL/6 splenocytes induce acute epithelial-tissue GvHD that is lethal over several months. 14 In contrast, high-dose C57BL/6 lymph node (LN) cells induces a BM failure type of GvHD (BMGvHD), which is rapidly lethal; [15][16][17] BMGvHD is also seen if recipients are irradiated, in which case lower quantities of C57BL/6 T cells are required. The characteristics of parent-in-F1 GvHD is equally known to vary between strain combinations, and to depend on strainspecific alloreactive T-cell-precursor frequency.…”